Artificial gut Simulator. A scheme to predict intestinal and plasma concentration–time profiles of a weakly basic BCS-II drug, dipyridamole

The objective of this study was to develop a scheme to predict intestinal and plasma concentration–time profiles of the weakly basic BCS-II drug, dipyridamole (DPD), using an Artificial Gut Simulator (AGS) integrated with a compartment-based disposition model. In vivo data for this study was obtained from previously published literature. A 3-compartment disposition model was developed using the plasma concentration–time profile of DPD following an intravenous bolus dose. The AGS, consisting of a donor cell and a hollow fiber-based absorption module, was tuned to absorb DPD saturated solution at a physiological rate constant, 0.0402 min⁻¹, based on the measured Caco-2 cell monolayer permeability coefficient. The dose dumping technique commonly used during dissolution testing can generate excessively high initial supersaturation and precipitation which is not physiologically relevant. In this study, fractions of DPD dose were added incrementally every 15 min to the AGS donor to simulate an overall first-order gastric emptying process. The concentration absorbed by the hollow fiber receiver media was input into the central compartment of the disposition model. The predicted plasma concentration–time profile matched the human in vivo profile of DPD obtained after oral administration of a 50 mg dose. For 30 and 90 mg oral doses, time profiles of concentration and fraction precipitated in the AGS donor agreed well with human duodenal measurements. This study demonstrates the significance of simulating physiological rate of absorption in vitro to accurately predict the bioavailability of a BCS-II compound.